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Bone morphogenetic protein 4 modulates melanocyte proliferation and melanogenesis

M. Yaar, H.Y. Park, V. Botchkarev, K. Stewart, I. Panova and B.A. Gilchrest. Boston Univ. School of Medicine, Boston, MA 02118

Bone morphogenetic proteins (BMP), originally characterized by their role in development of cartilage and bone, signal in many cells including neural precursors. To determine the BMP effect on neural crest-derived normal human melanocytes (Mc), Mc were stimulated with BMP4 (0-25 ng/ml). Within 72 hrs, BMP4 increased Mc yield by ~300% (p<0.03) and decreased melanin/cell by 75 1% (p<0.005). BMP4 does not affect Mc yield by inhibition of apoptosis, as there was no increase in cytoplasmic DNA-histone levels at 48 hrs or 72 hrs. BMP4 signaling involves two receptors: BMP R1and BMP R2. BMP R1 binds BMP, while BMP R2 transduces the signal. BMP R1 has two distinct forms: A and B. BMP R1A promotes neural precursor proliferation and BMP R1B promotes their mitotic arrest and differentiation. RT-PCR using primers complementary to these human receptor transcripts, confirmed by product sequencing, clearly demonstrated strong constitutive expression of the proliferation-associated BMP R1A in Mc. Mc also expressed BMP R1B and BMP R2, demonstrating that Mc express all transmembrane receptors required to respond to BMP stimulation. BMP signals are transduced through phosphorylation of cytoplasmic Smad proteins that translocate to the nucleus to affect gene transcription. The DNA consensus sequence recognized by Smad, cagaca, is present in the promoter region of human tyrosinase (nucleotides —2051 to -2045). Indeed, northern and western blot analyses of BMP4-treated Mc show substantially downregulated tyrosinase mRNA and protein, respectively, within15 hrs through 72 hrs. Interestingly, BMP4 also substantially downregulates the two PKC-b transcripts as well as PKC-b protein, the enzyme that activates tyrosinase. Intriguingly, by RT-PCR and sequencing we found that keratinocytes weakly express BMP4, but Mc strongly express BMP4, suggesting an autocrine effect of BMP4 on Mc. These data provide evidence of a novel signaling pathway that influences Mc function in human skin.